Kaposi's sarcoma-associated herpesvirus (KSHV) is a ubiquitous virus that establishes a life-long persistent infection in humans and is associated with Kaposi's sarcoma and several lymphoid malignancies. It has now become clear-following epidemiological, serological, and virological studies-that KSHV legitimately joins the ranks of EBV, CMV, and HHV-6 and-7 as a true oral herpesvirus. During latency, the KSHV genome persists as a multicopy circular DNA assembled into nucleosomal structures. While viral latency is characterized by restricted viral gene expression, reactivation induces the lytic replication program and the expression of viral genes in a defined sequential and temporal order. Our preliminary study demonstrates that (1) the latent and lytic chromatins of KSHV are associated with a distinctive pattern of activating and repressive histone modifications whose distribution changes upon reactivation in an organized manner in correlation with the temporally ordered expression of viral lytic genes. (2) It is intriguing to observe the unique epigenetic profiles of KSHV genome in oral epithelial cells where the KSHV genome primarily undergoes transcriptionally active euchromatin formation, leading to spontaneous lytic replication. (3) We have developed an infectious KSHV bacterial artificial chromosome (BAC16) and NOD/SCID IL2Rg-/- (NSG) humanized mouse model that allows efficient viral genetic manipulation and in vivo persistence study, respectively. Based on our preliminary studies, we hypothesize that the differential epigenetic modification of the KSHV genome is the crux of determining latent infection vs. lytic reactivation of in vivo viral lifecycle. We will investigate the transition mechanism between euchromatin and heterochromatin during de novo infection of various cells including oral epithelial cells, and utilize small molecule inhibitors, gene knockdown and mutants to alter the epigenetic modifications for KSHV lytic gene expression cascade and latency (Aim 1). Subsequently, we will define in vivo roles of the epigenetic modifications of the KSHV genome for viral persistence by utilizing NSG humanized mouse model (Aim 2). Thus, this study will show that histone-modifying enzymes involved in the regulation viral gene expression ultimately serves as pharmaceutical targets to control KSHV-associated oral complications.